US3939204A - Radioactive functional diagnostic agents - Google Patents

Radioactive functional diagnostic agents Download PDF

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Publication number
US3939204A
US3939204A US05/366,461 US36646173A US3939204A US 3939204 A US3939204 A US 3939204A US 36646173 A US36646173 A US 36646173A US 3939204 A US3939204 A US 3939204A
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compound according
iodine
hydrogen
carboxy
carbon atoms
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US05/366,461
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Gotz Buttermann
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides

Definitions

  • Triiodized N-methyldicarboxylic acid anilides useful as radiopaque agents are described in copending, commonly assigned U.S. patent application Ser. No. 281,379, filed Aug. 17, 1972, the contents of which are incorporated by reference herein.
  • This invention relates to triiodized carboxylic acid anilides and to processes for their preparation and use.
  • radioactively labeled compounds as auxilliary agents for the observation and explanation of biochemical processes has been known for a long time: For example, for the development of medicines and for diagnostic purposes; i.e., for the liver function test, tetrachlorotetraiodofluorescein-I 131 , bromthalein-I 131 , and gold colloid Au 198 have been employed. However, these compounds all exhibit various disadvantages.
  • bromthalein-I 131 as with tetrachlorotetraiodofluorescein-I 131 , the maximum accumulation in the liver and the elimination from the liver take place after a longer period of time, requiring longer examination times and a higher exposure to radiation.
  • Gold colloid Au 198 is only suitable for representing the liver by scintigraphy and does not provide a direct functional diagnosis.
  • dicarboxylic acid anilides containing radioactive iodine, of this invention, as well as the salts thereof with physiologically compatible bases, do not exhibit these disadvantages.
  • radioactive iodine isotope After being labeled with a radioactive iodine isotope, they represent excellent agents for the functional conductance of diagnostics on the hepatic cells themselves.
  • Another object of this invention is to provide a process for preparing radioactive triiodized dicarboxylic acid anilides in good yields.
  • a further object of this invention is to provide useful radioactive diagnostic compositions and methods for their use.
  • R 1 is hydrogen, carboxyl, N-acylamino, N-acylaminomethyl, N-alkyl-N-acylamino, N-butyrolactamyl, or an ##EQU2## group, wherein R 3 and R 4 are each hydrogen, lower alkyl of hydroxyalkyl, or R 3 and R 4 together with the nitrogen atom form a 5 to 7 member heterocyclic ring which can contain a further oxygen, nitrogen or sulfur hetero atom;
  • R 2 is hydrogen, lower alkyl or hydroxyalkyl
  • X is straight-chain or branched alkylene of 1-14 carbon atoms, which can be interrupted by one or more oxygen or sulfur atoms,
  • the compounds of this invention according to Formula I include both the free compounds and their metal, ammonium and amine salts, preferably the water-soluble and non-toxic physiologically acceptable salts. These compounds, individually or in admixture, are valuable radioactive agents.
  • dicarboxylic acid anilides containing radioactive iodine refers to compounds wherein 1-6 inclusive iodine 127 atoms are replaced by a radioactive iodine isotope, e.g., iodine 131 , iodine 123 , iodine 125 or iodine 132 .
  • the alkyl, alkoxy and acyl residues when present are preferably lower residues, e.g., lower alkyl of 1-6 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl or butyl; lower alkoxy of 1-4 carbon atoms, preperably 1-2 carbon atoms, such as methoxy or ethoxy; lower acyl, preferably lower alkanoyl of 1-6 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, valeryl and hexanoyl.
  • Preferred lower hydroxyalkyl groups are 2-hydroxyethyl or 3-hydroxypropyl.
  • Suitable salts of physiologically compatible bases include but are not limited to the alkali metal salts, e.g., sodium and lithium; the alkaline earth metal salts, e.g., calcium and magnesium; amine salts, e.g., ammonium, heterocyclic amines, e.g., morpholine and N-alkyl amines, hydroxyalkylamines, alkyl (hydroxyalkyl)-amines and di(hydroxyalkyl)-amines, wherein alkyl in each instance preferably contains 1-6, more preferably 1-4, carbon atoms, e.g., methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert.-butyl, including trimethylamine, diethylamine, ethanolamine, diethanolamine and polyhydroxyalkylamines, e.g., trihydroxy-tert.-butylamine, saccharidyl amines,
  • Preferred mono- and dialkyl glucamines are those compounds which contain, in one or both alkyl groups respectively, a total of 1-4 carbon atoms; a hydroxy group can also be present when the alkyl group of these salts contains more than one carbon atom.
  • Especially preferred alkylglucamine salts are the N-methyl and N,N-dimethyl salts.
  • compounds of Formula I are those in which R 1 is hydrogen, carboxyl, N-monoalkanoylamino, N-monoalkoxyalkanoylamino, N-alkyl-N-alkanoylamino, N-alkyl-N-alkoxyalkanoylamino, N,N-dialkanoylamino, N-alkanoylaminomethyl, ##EQU3## wherein A is alkylene of 2 or 3 carbon atoms and R 3 and R 4 are each hydrogen, lower alkyl or hydroxyalkyl, or R 3 and R 4 together with the nitrogen atom form a 5 to 7 member heterocyclic ring.
  • Preferred compounds of this invention are those of Formula I meeting one or more of the following definitions:
  • R 1 is hydrogen, carboxyl, N-lower alkanoylamino, N-lower alkyl-N-lower alkanoylamino, N-butyrolactamyl; N-lower-alkanoylaminomethyl;
  • R 2 is hydrogen, lower alkyl of 1-4 carbon atoms, 2-hydroxyethyl or 3-hydroxypropyl
  • R 3 and R 4 are each hydrogen, alkyl, of 1-4 carbon atoms, 2-hydroxyethyl or 3-hydroxypropyl;
  • Preferred dicarboxylic acid anilides are:
  • Equivalents of the compounds of this invention bearing a lower-alkanoyl group are compounds otherwise corresponding structurally thereto and possessing the same activity where instead of a lower-alkanoyl group there is present the acyl group of another organic acid, e.g., a carboxylic-acid containing up to 15 carbon atoms, especially aliphatic carboxylic, preferably an alkanoic acid, which can be unsaturated, branched, polybasic, or substituted in the usual manner, e.g., by hydroxy or halogen atoms; a cycloaliphatic, aromatic or mixed aromatic-aliphatic (alkaryl or aralkyl) acid, which can likewise be substituted in the usual manner, examples of preferred acids being formic acid, acetic acid, hydroxyacetic acid, propionic acid, butyric, isobutyric, ⁇ -ethylbutyric, valeric, isovaleric, ⁇ -ethylvaleric, 2-methylbut
  • the acyl group of such equivalent compounds can also be that of a sulfonic acid, e.g., an arylsulfonic, including benzenesulfonic, p-toluene-sulfonic, m,m'-dimethylbenzenesulfonic, o,o'-dimethylbenzenesulfonic, sym.-trimethylbenzenesulfonic, sym.-triethylbenzenesulfonic, m-ethylbenzenesulfonic, para-isopropylbenzenesulfonic, m-n-butylbenzenesulfonic acid, or an alkylsulfonic, e.g., methanesulfonic, ethanesulfonic, propanesulfonic, isopropanesulfonic, butanesulfonic, tert.-butanesulfonic, pentanesulfonic, is
  • the radioactive compounds of Formula I can be prepared either by radioactively labeling corresponding nonradioactive compounds or by synthesis from radioactive starting materials. While the radioactive iodines are greatly preferred for diagnostic agents, it will be apparent that other radioactive atoms can likewise be used depending on the type of radiation and radioactive half life suitable for a given purpose e.g., bromine-82, etc.
  • X has the above-indicated values and Hal is chlorine or bromine.
  • reaction of an acid of Formula II with a dicarboxylic acid derivative of Formula II is preferably effected in an inert solvent at elevated temperatures, e.g., at temperatures of 60° -140° C.
  • Suitable inert solvents include but are not limited to dioxane, toluene, dimethylformamide and dimethylacetamide.
  • the conventional pharmaceutical bases can be employed, especially sodium hydroxide, glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, etc.
  • the radioactive compounds of this invention are conveniently produced by heating one or more compounds of Formula I to be radioactively labeled in an aqueous solution or in a melt of one or more low-melting compounds with a maximally carrier-free alkali or alkaline earth radioiodide.
  • Suitable low-melting compounds include but are not limited to N,N-dimethyl-p-toluenesulfonamide, N,N'-bis(dimethylamino)-sulfone, dimethylsulfone, or mixtures thereof.
  • Suitable alkali or alkaline earth radioiodides include but are not limited to sodium, calcium etc.
  • the reaction is generally effected in the case of aqueous solutions at boiling temperature for a period of time sufficient to effect labelling, generally of 15 minutes to 12 hours, and using a molar ratio of radioiodide to the compound of Formula I which varies according to the desired degree of labelling.
  • the reaction is generally effected at a temperature of 50° to 300°C. for a period of time sufficient to effect labelling, generally of 15 minutes to 12 hours.
  • the compounds of this invention can be employed in mixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for intravenous administration, the soluble salts of this invention are preferably used in aqueous solution whereby the concentration of the salts is preferably about 0.1-50% by weight and wherein the radioactivity per ml. is 0.025- 25 mc, preferably 1-10 mc.
  • the acids in the form of their water-soluble, physiologically compatible salts, are extraordinarily good radioactive diagnostic agents for evaluating liver functions.
  • the salt solutions are characterized by a extremly low viscosity and accordingly can be administered by intravenous injection.
  • the salt solutions are furthermore distinguished by a good circulatory compatibility and a low toxicity.
  • the present invention also relates to a radioactive functional diagnostic agent, comprising an iodine-labeled dicarboxylic acid anilide of the general Formula I in the form of the water-soluble salts thereof with physiologically compatible bases, characterized in that it is present in the form of aqueous solutions containing per 10 ml. of water, 1 mg. to 5 g. of iodine-labeled dicarboxylic acid anilide, wherein the radioactivity per 1 ml. ranges between 0.025 mc. and 25 mc.
  • Compounds of Formula I are particularly useful in the preparation of a radioactive functional diagnostic agent comprising an iodine-labeled dicarboxylic acid anilide of Formula I, preferably in the form of the water-soluble salts thereof with physiologically compatible bases.
  • a radioactive functional diagnostic agent comprising an iodine-labeled dicarboxylic acid anilide of Formula I, preferably in the form of the water-soluble salts thereof with physiologically compatible bases.
  • 1 mg. to 5 g., preferably 10- 100 mg., of iodine-labeled dicarboxylic acid anilide and an equivalent amount of one or more physiologically compatible bases are dissolved, per 10 ml. of water, the solution is filled into ampoules or multivials and sterilized to provide a diagnostic agent wherein the radioactivity per 1 ml. ranges between 0.025 mc. and 25 mc., preferably 1- 10 mc.
  • radioactive compounds of this invention are normally present in combination with a major amount of the corresponding unlabeled compounds, since the labelling process is largely random and only a small percentage of the molecules need be labeled.
  • A diglycolic acid bis(3-carboxy-2,4,6-triiodoanilide)-131-iodine N-methylglucamine salt.
  • the table clearly shows the superiority of compound A of this invention as compared to the conventional compounds B and C.
  • the maximum accumulation of compound A in the liver occurs after only 16.5 minutes, and times of appearance in the intestine and gallbladder are also markedly shorter than in the comparison substances B and C.
  • the rapid elimination from the blood into the liver cells and from the liver cells into the bile ducts and gallbladder is demonstrated by the brief half-life periods T 1/2.
  • T 1/2 indicate a markedly faster liver passage for compound A, resulting in a better differentiated uptake curve and images of greater contrast. Because of this, the duration of the examination is shortened by one-third. Moreover, the rapid course of the liver passage function, together with the faster elimination, further reduces a patient's exposure to the radiation. Additionally, in the case of patients having a healthy liver, a concomitant gallbladder representation is obtained, in contrast to substances B and C; and it is thus possible to simultaneously obtain a gallbladder kinetics representation in a single diagnostic test.
  • compounds of Formula I are highly suitable as agents for evaluating the liver function, as well as for the representation and functional diagnosis of the bile ducts and the gallbladder.
  • 100 mg. of diglycolic acid bis(3-carboxy-2,4,6-triiodoanilide) methylglucamine salt is dissolved in 10 ml. of water at a pH of about 6.5, mixed with 1 ml. of sodium acetate buffer, and the desired activity quantity is added as an aqueous sodium iodide 131 solution -- maximally carrier-free, e.g., 10 mc.
  • the solution is heated under reflux for 15 minutes. After cooling, the solution is acidified with 2N hydrochloric acid, and the thus-precipitated product is vacuum-filtered.
  • the precipitated 131iodine-labeled diglycolic acid bis(3-carboxy-2,4,6-triiodoanilide) is again suspended in 10 ml. of water, dissolved with sodium hydroxide solution, and reprecipitated with hydrochloric acid.
  • the product in a more than 90% yield, chemically as well as radiochemically, is diglycolic acid bis(3-carboxy-2,4,6-triiodoanilide)-131-iodine.
  • any other radioactive iodine isotope such as I 123 , I 125 and I 132 .
  • Example 2 Analogously to Example 1, the following compounds can be labeled with 131-, 123-, 125- and 132 iodine:
  • An aqueous solution of sodium iodide 131, maximally carrier-free, containing 10 mc. is dried in a small flask under a nitrogen atmosphere. Thereafter, 100 mg. of N,N-dimethyl-p-toluenesulfonamide is added thereto and the mixture is heated to 120°C., until it melts. 25 mg. of diglycolic acid bis(3-carboxy-2,4,6-triiodoanilide) is added to the melt, and a clear melt is thus formed. After 1 hour, the melt is allowed to cool, the solidified mass is dissolved in 3 ml. of acetone, and stirred into ice-cooled aqueous ammonia solution.
  • diglycolic acid bis(3-carboxy-2,4,6-triiodo-N-methylanilide) and 3,6,9-trioxaundecane-1,11-dioyl bis(3-carboxy-2,4,6-triiodo-N-methylanilide) can be labeled with 131-, 123-, 125- and 132-iodine.
  • This solution is filled into a multivial and sterilized at 120° C.
  • the solution thus contains, at the time of preparation, 1 mc./ml.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US05/366,461 1972-12-22 1973-06-04 Radioactive functional diagnostic agents Expired - Lifetime US3939204A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE2264002 1972-12-22
DT2264002 1972-12-22
DE19732300966 DE2300966C3 (de) 1973-01-10 Radioaktives Jod (131-, 123-. 125- oder 132-Jod) enthaltende Dfcarbonsäureanilide, deren Metall- oder Aminsalze, Verfahren zur Herstellung dieser Verbindungen und diese enthaltende radioaktive Funktlonsdiagnostika
DT2300966 1973-01-10

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CA (1) CA979000A (ja)
CH (1) CH599121A5 (ja)
DD (1) DD104193A5 (ja)
FR (1) FR2211262B1 (ja)
GB (1) GB1427422A (ja)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4014986A (en) * 1974-05-31 1977-03-29 Laboratoires Andre Guerbet X-ray contrast media
US4021481A (en) * 1969-06-27 1977-05-03 Nyegaard & Co. A/S Amido derivatives of 2,4,6-triiodobenzoic acids containing at least one N-hydroxyalkyl and at least two hydroxyl groups
US4062934A (en) * 1975-06-04 1977-12-13 Laboratoires Andre Guerbet X-ray contrast media
US4065554A (en) * 1974-05-31 1977-12-27 Laboratoires Andre Guerbet X-ray contrast media
US4132731A (en) * 1976-06-25 1979-01-02 Schering Aktiengesellschaft Novel iodized isophthalamic acid compounds
US4225577A (en) * 1978-05-31 1980-09-30 Guerbet S.A. Ionic polyiodo benzene derivatives useful as X-ray contrast media
US4239747A (en) * 1976-06-23 1980-12-16 Schering Aktiengesellschaft Dicarboxylic acid bis(3,5-dicarbamoyl-2,4,6-triiodoanilides) useful as x-ray contrast agents
DE3015864A1 (de) * 1979-06-11 1980-12-18 Cincinnati Milacron Inc Diamide mit endstaendigen carboxylsaeure-gruppen
EP0022056A3 (en) * 1979-06-28 1981-03-25 Schering Aktiengesellschaft Berlin Und Bergkamen Dimers of tri-iodated isophthalic acid diamides, their preparation and x-ray contrast agent containing them
US4264572A (en) * 1978-11-30 1981-04-28 Schering Aktiengesellschaft X-ray contrast media
US4395391A (en) * 1980-11-25 1983-07-26 Schering Aktiengesellschaft Unsymmetrically substituted dicarboxylic-acid-bis-(2,4,6-triiodo-anilides), their preparation, and x-ray contrast media containing same
US5066823A (en) * 1987-05-22 1991-11-19 Bracco Industria Chemica S.P.A. Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives
US5123951A (en) * 1986-03-31 1992-06-23 Rhone-Poulenc Nederland B.V. Synergistic plant growth regulator compositions
US5349085A (en) * 1982-11-08 1994-09-20 Nycomed Imaging As X-ray contrast agents

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3038853A1 (de) * 1980-10-10 1982-05-27 Schering Ag, 1000 Berlin Und 4619 Bergkamen Neue n-hydroxy-alkylierte dicarbonsaeure-bis-(3,5-dicarbamoyl-2,4,6-trijodanilide), deren herstellung und diese enthaltende roentgenkonstrastmittel (ii)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3763227A (en) * 1967-12-28 1973-10-02 Pharmacia Ab Novel 3,5-substituted 2,4,6-triiodobenzoic acids and salts thereof
US3770820A (en) * 1967-05-11 1973-11-06 J Ackerman Iodinated anilic acids
US3804892A (en) * 1967-12-28 1974-04-16 Pharmacia Ab Novel 3,5-substituted 2,4,6-triiodobenzoic acids and salts thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3770820A (en) * 1967-05-11 1973-11-06 J Ackerman Iodinated anilic acids
US3763227A (en) * 1967-12-28 1973-10-02 Pharmacia Ab Novel 3,5-substituted 2,4,6-triiodobenzoic acids and salts thereof
US3804892A (en) * 1967-12-28 1974-04-16 Pharmacia Ab Novel 3,5-substituted 2,4,6-triiodobenzoic acids and salts thereof

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4021481A (en) * 1969-06-27 1977-05-03 Nyegaard & Co. A/S Amido derivatives of 2,4,6-triiodobenzoic acids containing at least one N-hydroxyalkyl and at least two hydroxyl groups
US4065554A (en) * 1974-05-31 1977-12-27 Laboratoires Andre Guerbet X-ray contrast media
US4065553A (en) * 1974-05-31 1977-12-27 Laboratoires Andre Guerbet X-Ray contrast media
US4014986A (en) * 1974-05-31 1977-03-29 Laboratoires Andre Guerbet X-ray contrast media
US4062934A (en) * 1975-06-04 1977-12-13 Laboratoires Andre Guerbet X-ray contrast media
US4239747A (en) * 1976-06-23 1980-12-16 Schering Aktiengesellschaft Dicarboxylic acid bis(3,5-dicarbamoyl-2,4,6-triiodoanilides) useful as x-ray contrast agents
US4132731A (en) * 1976-06-25 1979-01-02 Schering Aktiengesellschaft Novel iodized isophthalamic acid compounds
US4225577A (en) * 1978-05-31 1980-09-30 Guerbet S.A. Ionic polyiodo benzene derivatives useful as X-ray contrast media
US4264572A (en) * 1978-11-30 1981-04-28 Schering Aktiengesellschaft X-ray contrast media
DE3015864A1 (de) * 1979-06-11 1980-12-18 Cincinnati Milacron Inc Diamide mit endstaendigen carboxylsaeure-gruppen
DE3050184A1 (ja) * 1979-06-11 1982-07-29
EP0022056A3 (en) * 1979-06-28 1981-03-25 Schering Aktiengesellschaft Berlin Und Bergkamen Dimers of tri-iodated isophthalic acid diamides, their preparation and x-ray contrast agent containing them
US4395391A (en) * 1980-11-25 1983-07-26 Schering Aktiengesellschaft Unsymmetrically substituted dicarboxylic-acid-bis-(2,4,6-triiodo-anilides), their preparation, and x-ray contrast media containing same
US5349085A (en) * 1982-11-08 1994-09-20 Nycomed Imaging As X-ray contrast agents
US5123951A (en) * 1986-03-31 1992-06-23 Rhone-Poulenc Nederland B.V. Synergistic plant growth regulator compositions
US5066823A (en) * 1987-05-22 1991-11-19 Bracco Industria Chemica S.P.A. Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives

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FR2211262B1 (ja) 1976-04-09
CA979000A (en) 1975-12-02
JPS4988834A (ja) 1974-08-24
DD104193A5 (ja) 1974-03-05
AU5367273A (en) 1974-09-26
CH599121A5 (ja) 1978-05-12
FR2211262A1 (ja) 1974-07-19
GB1427422A (en) 1976-03-10

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